Abstract

The composition of the atherosclerotic lesion rather than the degree of stenosis is currently considered to be the most important determinant for acute clinical events. Modalities capable of characterizing the atherosclerotic lesion may be helpful in understanding its natural history and detecting lesions with high risk for acute events. Speaking grossly, three histologic features of the vulnerable plaque have been reported: size of the atheroma, thickness of the fibrous cap, and inflammation. Imaging techniques are currently being deployed and are under development to aid visualization of the vulnerable coronary plaque. Most of these diagnostic modalities have the potential to detect locally one or more of the three histologically defined features of vulnerable plaque. This review will focus on imaging techniques that have been developed to characterize the atherosclerotic lesion. Most catheter-based visualization techniques will provide insight into components of the local atherosclerotic plaque which may limit their predictive value for the occurrence of a clinical event. Therefore, the clinical relevance of these imaging tools will be discussed.

An imaging modality that is designed to visualize the coronary lumen is a diagnostic tool that depicts the outcome of atherosclerotic disease retrospectively. The percentage of luminal narrowing is a surrogate diagnostic measure for atherosclerosis, which itself is a disease of the arterial wall (1–4). Imaging techniques that visualize the coronary lumen have a low predictive value for the risk of acute occlusion (5–7).

The fine structure and composition of the atherosclerotic lesion, rather than the degree of stenosis, are currently considered to be the important determinants for acute clinical events, together with the absence of collateral circulation (1–4,9–12). Modalities capable of characterizing the tissue of the atherosclerotic lesion may help to understand its natural history and detect lesions with high risk for acute events.

This review will focus on techniques currently deployed and under development to visualize the vulnerable coronary plaque according to histologic characteristics, or identify the vulnerable plaque according to its chemical or physical properties. In addition, the clinical relevance of these imaging tools will be discussed.

The vulnerable lesion: structure and composition

The typical advanced atherosclerotic lesion is characterized by a core of extracellular lipid with an overlaying fibrous collagen-rich cap (1). The lipid core may contain layers of fibrous tissue. Atheromatous lesions with a sclerotic fibrous cap may transform into a complex type of lesion by rupture or erosion of the fibrous cap with subsequent formation of a thrombus. The lesion that is rupture prone is not clearly defined, but several morphologic and immunologic determinants specific for the vulnerable plaque have been reported (1–4,9–12). In order to evaluate the applicability of imaging techniques that are potentially capable of predicting which lesions may rupture, it is necessary to understand what specific features of the vulnerable lesion each of these techniques reveals. Grossly, there are three major, interrelated determinants of a plaque’s vulnerability to rupture.

Thickness of the fibrous cap

The cap overlying the atheromatous core consists of extracellular collagen-rich matrix and smooth muscle cells (Fig. 1). Fissures primarily occur in eccentric lesions at the shoulder region of the cap that is often thinnest with reduced collagen content (3). The peak circumferential stress is inversely related to cap thickness (13–15). When the fibrous cap is thin and a high circumferential stress at the luminal border of the plaque is present, plaque rupture is more likely to occur (16). Using finite element analysis, Loree et al. (14) showed that circumferential stress increases critically when cap thickness is less than approximately 150 μm. Hemodynamically related mechanical forces do not only directly induce plaque thinning but they also trigger release and/or activation of matrix degrading proteases (17) that degrade structural components within the fibrous cap (18).

Picro Sirius staining for collagen of atherosclerotic cross-sections. (A) Atherosclerotic plaque with a fibrous cap overlying lipid-rich areas. Thickness of the cap near the arrows is approximately 400 μm. (B) Atherosclerotic plaque with the atheroma adjacent to the lumen due to rupture of the thin fibrous cap. Thickness of the fibrous cap near the rupture (black arrows) is approximately 300 μm. (C) Rupture of the fibrous cap (black arrow).

Size and composition of the atheromatous lipid core

Plaques containing a highly thrombogenic lipid-rich core are more at risk for rupture if the size of the lipid core is large and is less consistent. Several investigators have reported on the relation of the amount of extracellular gruel and plaque fissuring (8,19,20). Davies et al. (8) estimated that when at least 40% of the plaque consists of lipid, an atheroma is at risk for rupture.

The consistency of the lipid core depends on lipid composition and temperature. A negative relation exists between temperature and core stiffness (21,22). If temperature increases, like with inflammation, the core becomes softer. Another determinant of plaque consistency is the composition of the atheroma: liquid cholesterol esters are softer than crystalline cholesterol. A soft core may be more vulnerable for rupture since it may not be able to bear the imposed circumferential stress, which is then redistributed to the fibrous cap where it may be critically concentrated (16).

Inflammation within or adjacent to the fibrous cap

Disruption of the fibrous cap is usually associated with heavy local infiltration by macrophages and often by T-lymphocytes. Activated macrophages are strongly colocalized with local thrombi as observed in patients who died of myocardial infarction (9). In addition, macrophages are more frequently demonstrated in coronary artery specimens obtained from patients suffering from unstable angina compared with patients with stable coronary artery syndromes (10).

Macrophages, but also other plaque-related cell types, may release matrix degrading proteases, the matrix metalloproteinases (MMPs) (8,23). The most frequently investigated MMPs with respect to plaque vulnerability (and atherosclerotis in general) are the collagenase MMP-1, the gelatinases MMP-2 and MMP-9 and stromelysin MMP-3. Matrix metalloproteinase-1 is colocalized with regions of high circumferential stresses, like the shoulders of an eccentric plaque (17); MMP-2 and MMP-9 are often studied in activity assays, zymography, and are associated with other histologic characteristics of the vulnerable lesion (18). In addition, their activity is enhanced in aortic aneurysms (24). By release of MMPs, macrophages initiate the degradation of fibrillar collagen that forms the skeleton of the fibrous cap.

Techniques characterizing the atherosclerotic vulnerable plaque

Choice, guidance and evaluation of an intervention technique are currently based on the routinely used visualization techniques like angiography and intravascular ultrasound. New diagnostic modalities may contribute to the understanding of the mechanisms underlying progression of atherosclerotic disease and plaque rupture, and lead to potential new therapeutic approaches aimed at the acute complications of atherosclerotic disease. Not only the degree of luminal stenosis but also the composition of the atherosclerotic plaque may determine the decision of which intervention type to use.

Most visualizing techniques that will be mentioned in this article are catheter based. Catheter-based techniques visualize the atherosclerotic plaque locally, which may limit clinical applicability, since it would be impractical and too time consuming to visualize all lesions in all coronary arteries. In addition, it should be critically appreciated that it is still unclear how clinical decision making will be influenced by these plaque characterization techniques, since etiologic research on the mechanism of plaque rupture and on the predictive values of a thin cap or a large atheroma for a plaque to rupture is lacking.

High-frequency (20 to 40 MHz) intravascular ultrasound

Intravascular ultrasound (IVUS) is a catheter-based imaging technique that provides two-dimensional cross-sectional tomographic images of the arterial wall (25). In vitro and in vivo studies have demonstrated the accuracy and reproducibility to assess quantitatively lumen area, plaque area and vessel area as well as morphologic features like calcifications and, after balloon angioplasty, the presence of dissections (25,26). Currently, IVUS is the only imaging modality that provides images in which variations in arterial geometry and atherosclerotic plaque along the artery can be studied in vivo (27–29).

The resolution of the ultrasound system is related to its frequency. Axial resolution is approximately 100 μm to 200 μm for 40-MHz and 20-MHz systems, respectively. Lateral resolution varies widely dependent on the beam width that is used but approximates 250 μm for 30 MHz. The penetration depth is inversely related to the frequency and is approximately 10 mm for a 30-MHz system. For high-frequency (40 to 50 MHz) systems, imaging may be hampered by an increased backscatter of blood.

Lipid-rich areas tend to appear as echolucent in the still frame IVUS image (25,30). However, the echo-lucency of these lipid lakes may depend on surrounding tissues (31). Histopathologic studies mostly report low sensitivities for IVUS in detecting lipid-rich lesions (30). A recent study, however, reports that the thickness of the fibrous cap and fractures with lipids protruding into the lumen were visualized (32), but no histologic validation was given. Only systems using frequencies of ≥40 MHz may allow reliable detection of thin fibrous caps, considering that the cap thickness in which circumferential stresses become critical may be <150 μm (14).

There are consistent reports on the association of calcifications and unstable syndromes: calcifications as observed in the IVUS image are more commonly observed in stable than in unstable syndromes (33,34).

Recent postmortem (35) and ultrasound studies (36–38) showed an intriguing relation between locally altered vessel size and histopathologic and clinical markers for plaque vulnerability. Thus, local arterial vessel size as measured with IVUS may be an indicator for lesion stability. Whether the mode of arterial remodeling and plaque vulnerability are related or associated remains to be investigated.

IVUS elastography

Ultrasound elastography is a new method to assess mechanical properties of parts of the atherosclerotic plaque (39–41). Tissue components that differ in hardness are expected to be compressed differently if a defined pressure is applied. As the response of tissue to mechanical excitation is a function of its mechanical properties, hard tissues (calcifications and collagen) will be compressed less than soft-tissue types (lipids) (39). From the radiofrequency data of two ultrasound images that have been obtained in a diastolic and systolic part of the heart cycle, strain images are constructed using the relative local displacements, which are estimated from the time shifts between gated echo-signals acquired. Hard and soft regions can be identified using this technique, while in the original image, it is not possible to discriminate the different tissue types (39). Recently, in vitro validation studies have been performed that demonstrated that elastography is capable of discriminating lipid-rich regions from fibrous regions within atherosclerotic cross-sections (40,41)(Fig. 2). The major advantage of the elastography technique is that it makes use of the radiofrequency data of the regular IVUS systems, which makes the introduction of another catheter redundant.

Echogram (upper panel, left), elastogram (upper panel, right) and histologic sections with alfa actin stain (left bottom panel), and picro Sirius red stain without (bottom middle panel) and with polarized light (bottom right panel) of a human femoral artery. The echogram reveals an eccentric plaque between the 2 and 11 o’clock position. The elastogram shows that the plaque can be divided into two parts: a low strain part (0.2%) between the 4 and 11 o’clock position and a high strain part (1.0%) between the 2 and 4 o’clock position, both compared to the moderate strain (0.5%) in the normal vessel wall. Histologic study reveals that the region between the 4 and 11 o’clock position is fibrous material and the region between the 2 and 4 o’clock position lacks smooth muscle cells (white arrow, left bottom panel) and collagen (white arrow right bottom panel) (with courtesy of C de Korte and T van der Steen, Erasmus University, Rotterdam).

Angioscopy

Angioscopy allows visualization of the plaque with high sensitivity. Owing to its color detection quality, thrombus is detected with high sensitivity (42). Plaque color on angioscopy is found to be closely related to clinical syndrome: yellow plaques are lipid rich and often associated with acute coronary syndromes (43,44). In addition, angioscopic identification of plaque rupture and subsequent thrombosis at the culprit lesions after catheter-based interventions is related to adverse outcomes (45). Angioscopic studies have improved the understanding of the mechanism of thrombolytic therapy after myocardial infarction when dissolving of the thrombus was visualized (46).

Still, the inability to examine the different layers within the arterial wall remains. Thus, no estimation of cap thickness or lipid content can be made making morphologic characterization of the plaque unreliable.

Magnetic resonance imaging

Magnetic resonance imaging (MRI) can be used to discriminate luminal boundaries by visualizing the blood flow. Magnetic resonance imaging studies are currently being performed to study the progression and regression of atherosclerotic plaques over time. High-resolution fast spin echo and optimized computer processing have enhanced the spatial resolution (0.4 mm) of visualizing atherosclerotic plaques in vivo. In experimental studies, the atherosclerotic lesions have been studied in hypercholesterolemic rabbits (47), pigs (48) and nonhuman primates (49). In genetically engineered mice, an excellent agreement was observed between high-resolution MRI (9T system, in plane spatial resolution 97 μm) and histopathology and demonstrated that in small animal models this technique can be used to monitor the development of atherosclerotic pathology over time and the response to therapy (50)(Fig. 3). In humans with carotid atherosclerosis, MRI was among the first noninvasive imaging techniques that allowed discrimination of lipid and fibrous tissues (51).

Magnetic resonance imaging of abdominal aorta (arrow) in normal mouse and apoE-KO mouse showing differences between normal and atherosclerotic arteries. On all MRIs, lumen is dark. Normal abdominal aorta wall thickness is approximately 50 μm and was not clearly visible at spatial in plane resolution of 97 μm. Wild-type mice were free of atherosclerotic lesions as shown on MRIs in A and B and histopathology (C). Large atherosclerotic lesion (arrow) that encircles the abdominal aorta of an apoE-KO mouse is shown on the MRI in D and E and was confirmed by histopathologic study (F). All MRIs have pixel size of 97 × 97 × 500 μm3 (adapted from Fayad et al [50]).

Theoretically, MRI is a promising noninvasive tool for detecting vulnerable plaques. At present, however, whole-body MRI at 1.5T lacks sufficient resolution (currently 400 μm) for accurate measurements of cap thickness and characterization of the atherosclerotic lesion within the coronary circulation. To improve the signal-to-noise ratio, an intravascular catheter coil has been developed that enhances image resolution to 250 to 300 μm. This intravascular MRI technique shows an 80% agreement with histopathology in analysis of intimal thickness and accurately determines plaque size (52). However, this resolution would still be too limited to determine cap thickness accurately. More recent studies have reported in-plane resolutions of 117 × 156 μm (53) for high-resolution intravascular MRI imaging, which is comparable to resolutions as obtained with IVUS. Thus, although difficulties remain with in vivo imaging, it may be a matter of time before MRI is used for identification of vulnerable plaques in human coronary artery disease.

Nuclear scintigraphic imaging techniques

Scintigraphy is based on the specific binding of radioactive labeled molecules to the target tissue, in this case the atherosclerotic rupture-prone lesion. According to Vallabhajosula and Fuster (54), the ideal radiotracer for visualizing the vulnerable plaque should meet the following criteria:

1. it must be specific for lipid core, macrophage density or thrombus;

2. it must be able to detect lesions in all atherosclerotic artery types that are related to clinical symptoms;

3. it must be able to assess progression-regression of atherosclerosis;

4. it must be able to predict clinically significant events;

5. it must be able to provide prognostic indicators in population studies; and

6. it must have a kit formulation for instant preparation, high specificity and sensitivity, fast blood clearance and high lesion to blood ratios.

There are no single radiotracers that meet all these criteria. In vivo studies have been performed using radiolabeled low-density lipoprotein which accumulates in the atherosclerotic plaque (55). Another in vivo tested label is IgG immunoglobulin which recognizes most atherosclerotic lesions but which is not specific for certain advanced stages of atherosclerotic disease (56,57). Circumventing the problem of nonspecific localization of IgG, a mouse/human chimerical monoclonal IgM antibody fragment with specificity for an antigen associated with proliferating smooth muscle cells has been studied in human atheroma (58). These aforementioned radiotracers, however, are not specifically related to rupture-prone plaques. Radiolabeled peptides incorporated specifically in mural thrombi may prove to be more clinically applicable (59,60).

Thermometry

Hypothetically, temperature measurements can be used to detect local inflammatory processes in the arterial wall. The thermistor is capable of measuring temperatures superficially with an accuracy of ≤0.1°C. Casscells et al. (61) showed in a freshly obtained carotid endarterectomy specimen a temperature rise up to 2.2°C in macrophage-rich areas. In that study, a significant correlation was observed between macrophage density and local temperature. More recently, the first study on in vivo assessment of local thermal heterogeneity in the coronary artery has been reported. Stefanadis et al. (62) recently reported temperature differences in the arterial wall in vivo using a thermistor on a 3F catheter with a 0.05°C accuracy and a spatial resolution of 500 μm. In a study of 90 patients, they observed higher temperatures of the coronary arterial wall in lesions of patients suffering from unstable angina and myocardial infarction compared with lesions studied in patients with stable angina (62).

Optical coherence tomography (OCT)

Optical coherence tomography has been successfully applied as an imaging tool in ophthalmology (63) and is now being investigated for its potential as an intravascular imaging device (64). The principle of OCT is similar to that of ultrasound imaging. A beam of low coherent infrared laserlight rather than sound is directed and reflected within the tissue.

Intravascular OCT catheters have been developed and applied in animal experiments in vivo. The intravascular device is capable of visualizing the atherosclerotic lesion with an axial resolution of 2 to 30 μm depending on the spectral width of the source and a lateral resolution of 5 to 30 μm determined by the beam waist (Fig. 4). The current penetration depth is limited to 1 to 2 mm. A trade-off exists between resolution and the penetration depth. In vitro validation studies revealed that OCT is capable of differentiating lipid tissue from water-based tissues (64). In addition, the thickness of the fibrous cap overlying an atheroma can be demarcated by OCT (64). Compared with IVUS, OCT provides a sharper delineation between intimal wall and plaque with collections of lipid (65).

Because of its high resolution and the fact that this technique can be easily incorporated into a thin catheter, OCT is a promising imaging modality for plaque characterization, although successful clinical application of the OCT may be hampered by the low penetration depth and the absorbance of light by blood.

Raman spectroscopy

Raman spectroscopy may be considered the acquisition of a molecular fingerprint. This characteristic makes Raman spectroscopy ideal for identifying gross chemical changes in tissue, such as in atherosclerosis (66). Raman spectra are collected as follows: light of a single wavelength from a laser is directed onto the tissue sample via glass fibers. Light scattered from the sample is collected in fibers and launched into a spectrometer. The plot of signal intensity as a function of wavelength (or frequency) can be obtained in a few seconds (67). To extract clinically useful information from these spectra, spectral modeling is performed (68,69). In vitro studies have demonstrated that diagnostic algorithms allow the discrimination of coronary arterial tissue in three categories: nonatherosclerotic, noncalcified plaque and calcified plaque (68).

Penetration depth of the Raman spectroscopy in arterial tissue is reported to be 1.0 to 1.5 mm. This would allow the Raman technique to examine tissue types beneath fibrous caps and within the atheromatous core. If one properly accounts for the depth of a cholesterol deposit into an arterial wall, it has been shown that cholesterol amounts calculated with spectra correlate strongly to amounts determined with quantitative microscopy (70).

Current limitations of Raman spectroscopy are the strong background fluorescence and the absorbance by blood of the laser light. In addition, information on plaque configuration is lost. The combination of Raman spectroscopy with IVUS or OCT into one catheter may be attractive since information on the chemical composition and tomography of the plaque would be obtained simultaneously (Fig. 5).

Intravascular ultrasound image of a calcified coronary artery (left), and the relative weights of calcium salts (top) and total cholesterol (bottom) in the same artery plane determined by Raman spectroscopy. The IVUS images were obtained from an intact artery segment, which were marked by a needle (12 o’clock). Raman spectra were obtained from the artery after the artery was opened. The IVUS image shows a calcification, in agreement with the calcium salts detected with Raman spectroscopy. Cholesterol was detected with Raman spectroscopy but could not be discriminated within the IVUS image (with courtesy of R Buschman and TJ Römer, Leiden University Medical Center).

Thus, intravascular Raman spectroscopy is an imaging modality in an early stage of development that has great potential to discriminate in vivo among lipid-rich, calcified and fibrotic plaques.

The aforementioned techniques are just a selection of the imaging modalities currently used in vivo or that are in a validation stage. Electron-beam CT is a noninvasive detection method if calcifications are considered a surrogate end point of clinically relevant coronary artery disease. However, even with people who have a family history of heart disease, other risk factors tend to predict cardiac events better than the calcium score (71). In addition, positron emission tomographic scan has been mentioned as a method to identify inflammatory regions (61). Finally, in animal and postmortem validation studies, near-infrared spectroscopy (72), time-resolved laser-induced fluorescence spectroscopy (73) and electrical impedance measurements (74,75) were able to detect plaques with a thin cap and a large lipid pool with high sensitivity.

Plaque “imaging” modalities: a role in clinical decision making or experimental toy?

Most techniques mentioned in this article have the potential to locally detect one or more of the three determinants (atheroma, cap thickness and inflammation) of the vulnerable plaque. Most techniques specifically address the characterization of plaque content (IVUS, MRI, Raman, impedance). Optical coherence tomography is the only modality that has the resolution to focus on cap thickness, whereas elastography uses local compression as a surrogate for cap thickness and plaque composition. Local temperature is thus far the only measure of inflammation within the arterial wall. Except for MRI and scintigraphy, all visualization techniques require invasive intravascular catheter intervention.

For the clinician, the question is: what do these techniques contribute to the understanding (etiology), diagnosis and treatment/prevention of coronary artery disease?

Before a modality that aims to characterize the vulnerable plaque will have diagnostic or prognostic value, several hurdles need to be taken.

First, validation of the imaged features like cap thickness, plaque type and inflammation on a histologic resolution level is obligatory. Interpretations of imaged features like a “lipid lake” or a “fibrous cap” must not only be based on the priori knowledge of the expected localization of that feature within the image but also on histology like validation. Secondly, the modality should be made safely applicable for in vivo studies, preferably for the coronary circulation. Thirdly, the predictive value of the vulnerable plaque determinants for a plaque to rupture needs to be investigated first. Until now, to our knowledge, no studies have been performed on the predictive value of each of the three markers for a plaque to rupture (e.g., inflammation, large atheroma and thin fibrous cap). This third hurdle brings up another question which may result in a vicious circle: how is plaque rupture assessed retrospectively? Thus, the fourth hurdle is to find a diagnostic measure of plaque rupture. It will not be feasible to determine the occurrence of plaque rupture on a tissue level in a large clinical study. Therefore, surrogate end points must be searched for, like rapid acceleration of luminal narrowing on angiography or IVUS.

Finally, in a prospective study, the determinants of plaque rupture should be related to the incidence of acute events, taking into account the role of collateral circulation.

It is not likely, however, that a high predictive value of one of the visualized markers for plaque rupture will subsequently implicate a high diagnostic or prognostic value for the occurrence of a clinical event for two reasons. First, most visualization techniques will provide insight into components of the atherosclerotic plaque locally. It is reasonable to expect that visualization techniques will be guided toward lesions of angiographic interest and thus toward hemodynamically significant lesions. However, since lumen size is not related to local plaque vulnerability (5–7,35) only visualization of all atherosclerotic lesions throughout the entire coronary tract will provide insight into the “vulnerable state” of the major coronary branches. It is not practical to catheterize all coronary arteries and characterize all lesions. Secondly, inflammation and probably also other markers for plaque vulnerability are frequently and commonly observed features throughout the coronary arterial system (76). It is therefore unlikely that presence of a vulnerability marker has a high prognostic value for the occurrence of a clinically significant plaque rupture. The prognostic value of either a large atheroma or a thin fibrous cap is also impaired by the fact that part of the acute cardiac events are caused by local erosion of the plaque rather than rupture (9). Thus, although in the future catheter-based visualization techniques might allow vulnerability characterization of individual lesions, they may not provide prognostic estimates for the occurrence of a clinical event.

Techniques that allow detection of the three histologic markers for vulnerable plaques locally will certainly contribute to the understanding of serial events occurring in atherosclerotic disease by elucidating the predictive value of each of the potential markers for a plaque to rupture. However, local plaque composition may change over time with alteration of biochemical, dietary or environmental influences. A static measurement may therefore still have limited predictive value for local plaque rupture.

Techniques that are capable of characterizing the determinants related to plaque vulnerability may also contribute to the understanding of how pharmacological treatment, like, for example, statins, improve clinical outcome. The techniques are likely to further elucidate the effects of treatment on inflammation, reduction of atheromatous plaque mass, endothelial function or improved geometric remodeling (77–79).

The aforementioned described imaging techniques aim on visualizing the vulnerable rupture prone plaque locally. With most of these techniques intravascular catheter intervention is inevitable. It is less invasive to collect blood samples and determine systemic markers that are considered a surrogate end point for plaque vulnerability (80,81). However, since a clinical event is due to a local obstruction of the lumen and considering that plaque rupture may be a common feature in atherosclerotic disease, it is hard to understand how a systemic value of a marker for inflammation can be an accurate predictor for the occurrence of a locally determined clinical event. A systemically determined marker may be considered as a surrogate end point for the vulnerable state of atherosclerotic plaques throughout the circulation. The occurrence of a clinical event, then, is a matter of chance: the more vulnerable lesions are present throughout the coronary circulation, the more plaques may rupture with subsequent thrombotic occlusion of the lumen. Thus, where local imaging techniques may help understand the etiology of atherosclerotic luminal narrowing locally, systemic markers seem to have more potential when it comes to identification and prognosis of the patient with rupture-prone plaques.

Conclusion

Imaging modalities that aim to detect the vulnerable, rupture-prone lesion primarily focus on three postmortem observed determinants that have been identified in ruptured plaques: thickness of the fibrous cap, the extent of the atheromatous core and local inflammation. The highest resolutions are achieved by catheter-based techniques. Except for OCT, however, the resolution of current techniques is still too limited to discriminate the thin fibrous cap. The noninvasive imaging modalities like MRI suffer from inadequate resolutions, but their unlimited penetration depth and noninvasive nature are advantages. Imaging techniques that visualize the plaque locally may provide new insight into the etiology of sudden progression of atherosclerotic disease or acute events. However, due to their local applicability, it is not expected that they will have prognostic properties for the development of acute clinical syndromes that often originate from nonhemodynamically significant lesions. Therefore, systemic markers for inflammation may have more prognostic value for the identification of patients suffering from clinical events as a result of plaque rupture.

Acknowledgements

Ton van Leeuwen and Job Perree, Rick Buschman, Chris De Korte and Maurits Konings are gratefully acknowledged for their comments on the paragraph on OCT, Raman, elastography and impedance, respectively.

(1994) Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation89:36–44.

(1993) Evaluation of Indium-111-polyclonal immunoglobulin G to quantitate atherosclerosis in Watanabe heritable hyperlipidemic rabbits with scintigraphy: effect of age and treatment with antioxidants or ethinylestradiol. J Nucl Med34:1316–1321.

(1999) Inflammation of the atherosclerotic cap and shoulder of the plaque is a common and locally observed feature in unruptured plaques of femoral and coronary arteries. Arterioscl Thromb Vasc Biol19:54–58.

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